Lung cancer is one of the most commonly fatal human tumors. Many genetic alterations associated with the development and progression of lung cancer have been reported. Genetic changes can aid prognostic efforts and predictions of metastatic risk or response to certain treatments. (Mitsudomi T et al., (2000) Clin Cancer Res 6: 4055-63; Niklinski et al., (2001) Lung Cancer. 34 Suppl 2: S53-8; Watine J. (2000) Bmj 320: 379-80). Non-small cell lung cancer (NSCLC) is by far the most common form of lung cancer, accounting for nearly 80% of lung tumors (Society, A. C. Cancer Facts and FIGS. 2001, 2001). The overall 10-year survival rate remains as low as 10%, despite recent advances in multi-modality therapy, because the majority of NSCLCs are not diagnosed until advanced stages (Fry, W. A. et al., (1999) Cancer. 86: 1867-76). Although chemotherapy regimens based on platinum are considered the reference standards for treatment of NSCLC, those drugs are able to extend survival of patients with advanced NSCLC only about six weeks (Non-small Cell Lung Cancer Collaborative Group, (1995) BMJ. 311: 899-909). Numerous targeted therapies are being investigated for this disease, including tyrosine kinase inhibitors; however, to date promising results have been achieved in only a limited number of patients and some recipients suffer severe adverse reactions (Kris M G, et al., (2002) Proc Am Soc Clin Oncol. 21: 292a(A1166)).
It has been demonstrated that CD8+ cytotoxic T lymphocytes (CTLs) recognize epitope peptides derived from tumor-associated antigens (TAAs) presented on MHC class I molecules, and lyse the tumor cells. Since the discovery of the MAGE family as the first example of TAAs, many other TAAs have been discovered using immunological approaches (Boon T. (1993) Int J Cancer 54: 177-80; Boon T. et al., (1996) J Exp Med 183: 725-9; van der Bruggen P et al., (1991) Science 254: 1643-47; Brichard V et al., (1993) J Exp Med 178: 489-95; Kawakami Y et al., (1994) J Exp Med 180: 347-52). Some of them are now in clinical development as targets of immunotherapy. TAAs discovered so far include MAGE (van der Bruggen P et al., (1991) Science 254: 1643-7), gp100 (Kawakami Y et al., (1994) J Exp Med 180: 347-52), SART (Shichijo S et al., (1998) J Exp Med 187:277-88), and NY-ESO-1 (Chen Y. T. et al., (1997) Proc. Natl. Acd. Sci. USA, 94: 1914-8). On the other hand, certain gene products demonstrated to be somewhat specifically over-expressed in tumor cells have been shown to be recognized as targets inducing cellular immune responses. Such gene products include p53 (Umano Y et al., (2001) Br J Cancer, 84:1052-7), HER2/neu (Tanaka H et al., (2001) Br J Cancer, 84: 94-9), CEA (Nukaya I et al., (1999) Int. J. Cancer 80, 92-7) and the like.
Despite significant progress in basic and clinical research concerning TAAs (Rosenberg S A et al., (1998) Nature Med, 4: 321-7; Mukherji B. et al., (1995) Proc Natl Acad Sci USA, 92: 8078-82: Hu X et al., (1996) Cancer Res, 56: 2479-83), only a very limited number of candidate TAAs suitable for treatment of adenocarcinomas, such as lung cancer, are available. TAAs that are abundantly expressed in cancer cells, and whose expression is restricted to cancer cells, would be promising candidates as immunotherapeutic targets.
It has been repeatedly shown in 51Cr-release assays that peptide-stimulated peripheral blood mononuclear cells (PBMCs) from certain healthy donors produce significant levels of IFN-γ in response to the peptide, but rarely exert cytotoxicity against tumor cells in an HLA-A24 or A0201 restricted manner (Kawano K et al., (2000) Cancer Res 60: 3550-8; Nishizaka et al., (2000) Cancer Res 60: 4830-7; Tamura et al., (2001) Jpn J Cancer Res 92: 762-7). However, both HLA-A24 and HLA-A0201 are common HLA alleles in Japanese and Caucasian populations (Date Y et al., (1996) Tissue Antigens 47:93-101; Kondo A et al., (1995) J Immunol 155:4307-12; Kubo R T et al., (1994) J Immunol 152: 3913-24; Imanishi et al., Proceeding of the eleventh International Histocompatibility Workshop and Conference Oxford University Press, Oxford, 1065 (1992); Williams F et al., (1997) Tissue Antigen 49:129). Thus, antigenic peptides of cancers presented by these HLA alleles may be especially useful for the treatment of cancers among Japanese and Caucasian patients. Further, it is known that the induction of low-affinity CTL in vitro usually results from the use of peptide at a high concentration, generating a high level of specific peptide/MHC complexes on antigen-presenting cells (APCs), which will effectively activate these CTL (Alexander-Miller et al., (1996) Proc Natl Acad Sci USA 93: 4102-7).
Recent developments in cDNA microarray technologies have enabled the constructions of comprehensive profiles of gene expression of malignant cells as compared to normal cells (Okabe, H. et al., (2001) Cancer Res., 61, 2129-37; Lin Y M. et al., (2002) Oncogene, 21; 4120-8; Hasegawa S. et al., (2002) Cancer Res 62:7012-7). This approach enables an understanding of the complex nature of cancer cells and the mechanisms of carcinogenesis and facilitates the identification of genes whose expression is deregulated in tumors (Bienz M. et al., (2000) Cell 103, 311-320). Among the transcripts identified as commonly up-regulated in lung cancers, TTK (TTK Protein kinase; GenBank Accession No. NM—003318; SEQ ID Nos. 1, 2), URLC10 (cDNA for differentially expressed CO16 gene; GenBank Accession No. AB105187; SEQ ID Nos.3, 4) and KOC1 (IGF II mRNA Binding Protein 3; GenBank Accession No. NM—006547; SEQ ID Nos.5, 6) are of particular interest to the present inventors, being specifically up-regulated in tumor cells of the lung cancer tissues in more than 80% of the cases analyzed. In contrast, Northern blot analysis demonstrated that these gene products are not found in normal vital organs (See WO2004/031413, the entire contents of which are incorporated by reference herein). Thus, immunogenic peptides derived from TTK, URLC10 and KOC1 may find utility in killing tumor cells expressing those antigens. The present invention addresses these and other needs.